What is New in the 2015 WHO Lung Cancer Classification? Zhaolin Xu, MD, FRCPC, FCAP

What is New in the 2015 WHO Lung Cancer Classification? Zhaolin Xu, MD, FRCPC, FCAP Professor, Dept of Pathology, Dalhousie University, Canada Pulmonary Pathologist and Cytopathologist, QEII HSC Senior Scientist, Beatrice Hunter Cancer Research Institute

DISCLOSURE No conflict of interest

Objectives: To review the changes in the 2015 lung tumor classification To describe the diagnostic criteria for the new entities in lung adenocarcinoma To emphasize the importance of molecular profiling in lung cancer

WHO Lung Adenocarcinoma 1967 1981 2004 2015 Acinar Acinar ADC Mixed Lepidic Papillary Papillary ADC Acinar Acinar BAC BAC Papillary Papillary Solid with mucus BAC Micropapillary Non-mucinous Solid Mucinous Invasive mucinous Mix Colloid Solid with mucin Fetal Fetal Enteric Mucinous (Colloid) Minimally invasive Mucinous cystade AIS Signet-ring Non-mucinous Clear-cell Mucinous

Preinvasive lesions For adenocarcinoma Atypical adenomatous hyperplasia Adenocarcinoma in situ Non-mucinous Mucinous For squamous cell carcinoma Squamous cell carcinoma in situ For neuroendocrine tumors Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

Atypical adenomatous hyperplasia

Adenocarcinoma In Situ

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

Minimally invasive 3 cm solitary tumor with a predominantly lepidic pattern Invasive component 0.5 cm Usually non-mucinous Excluded if: invading lymphatc, blood vessels, air spaces or pleura presence of tumor necrosis spread through air spaces

Minimally invasive

Lepidic adenocarcinoma Predominantly lepidic pattern with invasive component > 0.5 cm Non-mucinous Invasive component: histologic pattern other than lepidic myofibroblastic stroma invading lymphatc, blood vessels, air spaces or pleura presence of tumor necrosis spread through air spaces Solitary tumor > 3 cm with lepidic pattern

Micropapillary adenocarcinoma Predominantly micropapillary pattern Papillary tufts without fibrovascular cores Tumor cell clusters may float within the alveolar spaces and/or connected to alveolar walls Vascular and stromal invasion is common Psammoma bodies may be present

Micropapillary adenocarcinoma

Solid adenocarcinoma Predominantly solid pattern If 100% solid 5 tumor cells with intracytoplasmic mucin in each of two high-power fields, or Positive for TTF-1 and/or napsin A It must be distinguished from squamous cell carcinoma and large cell carcinoma

Solid adenocarcinoma

Invasive mucinous adenocarcinoma Most common a lepidic pattern although other patterns can be seen except for a solid pattern It also includes cases formerly classified as mucinous BAC Mucinous cells with basally located nuclei Nuclear atypia is inconspicuous or absent Alveolar spaces often fill with mucin

Invasive mucinous adenocarcinoma adenocarcinoma

Colloid denocarcinoma

Enteric adenocarcinoma It resembles colorectal adenocarcinoma The enteric pattern > 50% IHC may be identical to or different from colorectal adenocarcinoma (CK7, CK20, CDX2, TTF-1) Clinical correlation

Enteric adenocarcinoma

WHO Lung Squamous Cell Carcinoma 1967 1981 2004 2015 Epidermoid Sq Ca (epidermoid) Sq Ca Papillary Keratinizing Sq Ca Non-keratinnizing Spindle cell Clear cell Bsaloid Small cell Basaloid

Basaloid squamous cell carcinoma

WHO Large Cell Carcinoma 1967 1981 2004 2015 Large cell Large cell Large cell Large cell Giant cell LCNEC Clear cell Basaloid Lymphoepithelioma-like Clear cell Rhabdoid

WHO Small Cell Carcinoma 1967 1981 2004 2015 Small cell anaplastic Small cell Small cell Small cell Oat cell Combined Combined Intermediate cell Combined

NUT carcinoma An aggressive tumor with NUT (nuclear protein in testis) gene rearrangement t(15;19), t(15;9) Sheets and nests of monomorphic small to intermediate cells Abrupt foci of keratinization Positive for NUT antibody, CK, P63/P40, CD34 May also positive for neuroendocrine markers, TTF-1

NUT carcinoma

Sclerosing pneumocytoma Previous known as sclerosing hemagioma A tumor of pneumocyte origin 80% in female, high incidence in East Asian A combination of solid, papillary, sclerotic, hemorrhagic patterns Two cell types: cuboidal surface cells and stromal round cells IHC Surface cells: CK+, CK7 +, TTF-1+, napsin A+, EMA+ Round cells: TTF-1+, EMA+, napsin A+/-, CK-

Sclerosing pneumocytoma

PEComatous tumors Arising from perivascular epithelioid cells (PEC) Three forms IHC Lymphagioleiomyomatosis (LAM) PEComa (clear cell tumor) Benign Malignant A diffuse proliferation with overlapping LAM and PEComa LAM: HMB45+, melan A+, α-actin+, ER+, PR+, β- catenin+, S100- PEComa: HMB45+, melan A+, S100+, PAS/D

Lymphagioleiomyomatosis

PEComa

Erdheim-Chester disease It is a xanthogranulomatous histiocytosis BRAF mutation >50% cases Involving skeleton, kidney, heart, lung, CNS Foamy histiocytic infiltrate along lymaphatic distribution with fibrosis, inflammatory cells, Touton giant cells IHC: CD68, Factor XIIIa, lysozyme, CD4, S100, alpha-antitrypsin, alpha-antichymotrypsin

Erdheim-Chester disease

Pulmonary myxoid sarcoma with EWSR1-CREB1 translocation Arising in the airways, often seen in young female Lobules of lacelike strands, cores of mildly atypical round, spindle or stellate cells with a myxoid stroma EMA 60% focal and weak+, others markers- EWSR1-CREB1 fusion gene detected by FISH, RT- PCR or direct sequencing

Pulmonary myxoid sarcoma with EWSR1-CREB1 translocation

Myoepithelial tumors Myoepithelial differentiaiton Benign and malignant Epithelioid, spindled, or plasmacyotid cells with uniform nuclei, eosinophilic or clear cytoplasm Cytoplasmic hyaline inclusions may be present Tumor cells arraanged in trabecular and/or reticular patterns with myxoid stroma IHC: CK+, S100+, calponin+, GFAP+, actin+, P63/P40+/-, desmin-, CD34- EWSR1 gene rearrangement

Myoepithelial tumors

Lung cancer survival rates 100 80 % 60 40 Cases 5 y survival 20 0 A B C D E Blue cases Red -5 year survival A Localized B Regional node metastasis or directly beyond primary site C - Distant metastasis D - Unknown stage E - Overall Median survival 8 months, 1 year survival 30 % Schiller JH et al. NEJM Jan. 2002

What do we learn from the history? Surgical treatment is effective but has limitations Majority of the lung cancer cases with no surgical indications at the time of diagnosis Chemotherapy / radiation is palliative Solutions Prevention Early detection New modalities

EGFR mutations EGFR mutations TKIs gefitinib, erlotinib, afatinib, AZD9291, CO-1686 ORR 68%, DCR 86%, median PFS 12 m, OS 23.3 m PFS, quality of life, safety profile, convenience EGFR exon 19 deletion in which afatinib vs chemotherapy median survival 31.7 : 20.7 m p<0.0001 ALK gene rearrangement ALK TKI crizotinib, ceritinib, alectinib In 1 st line setting vs chemotherapy: ORR 74% vs 45%, PFS 10.9 vs 7.0 m, but no OS benefit Phase 3 in 2 nd line setting vs chemotherapy: ORR 65% vs 20%, PFS 7.7 vs 3.0 m but no OS benefit

Prospective cancer classification